Argon has recently come into scientific focus as a
neuroprotective agent. The underlying neuroprotective mechanism remains unknown although
toll-like receptors were recently suggested to play an important role. We hypothesized that TLR-associated downstream
transcription factors are responsible for
argon's effects, leading to anti-apoptotic and anti-inflammatory properties. Apoptosis was induced in human
neuroblastoma cells. Immediately afterwards,
argon treatment (75 Vol% for 2 h) was initiated. Cells were analyzed, measuring mitochondrial membrane potential,
reactive-oxygen-species,
annexin-V/
propidium iodide staining,
transcription factor phosphorylation and binding activity as well as
protein and
mRNA expression of
interleukins.
Argon's in vivo effects were analyzed by quantification of retinal ganglion cell density,
mRNA expression, serum
cytokine analysis and immunohistochemistry after
retinal ischemia reperfusion injury (IRI) in rats.
Argon diminished
rotenone-induced kappa-light-chain-enhancer' of activated B-cells (NF-κB) and
signal transducer and activator of transcription 3 (STAT3) but not STAT5 or
cAMP-response element-binding protein (CREB) phosphorylation and
DNA-binding activity.
Argon treatment attenuated apoptosis by preservation of mitochondrial membrane potential and decline in
reactive oxygen species (ROS) generation. NF-κB and STAT3 inhibition, as well as TLR2 and TLR4 inhibition reversed
argon's effects on
IL-8 mRNA expression.
Argon attenuated
rotenone-induced
IL-8 protein and
mRNA expression in vitro. Inhibition of TLR2 and 4 attenuated
argon's protective effect in vivo reducing IRI driven
retinal IL-8 expression.
IL-8 expression was found in the retina in co-localization with Müller cells and retinal ganglion cells.
Argon mediates its
neuroprotective effects by TLR-mediated regulation of
transcription factors NF-κB and STAT3, thus decreasing
interleukin-8 expression in vitro and in vivo. These findings may open up new opportunities to effectively treat
cerebral ischemia and
reperfusion injury through the inhalation of
argon.
Argon exerts its protective effects in vitro and in vivo via
toll-like receptors TLR2 and TLR4 signaling, followed by alteration of downstream
enzymes. In conclusion,
argon mediates its beneficial effects by suppression of STAT3 and NF-κB phosphorylation and subsequent suppression of
interleukin IL-8 protein expression. These novel findings may open up opportunities for
argon as a therapeutic agent, particularly in the treatment of neuronal injury. Cover image for this issue: doi: 10.1111/jnc.13334.